At present, there are about 300 million people worldwide suffering from asthma. It is predicted that the prevalence will go up to 400 million in 2025. Currently, there are three anti-inflammatory agents for controlling asthma, which include inhaled steroids, cysteinyl-leukotriene receptor antagonist and cromolyn. However, the therapeutic efficacies of cysteinyl-leukotriene receptor antagonist and cromolyn are highly variable and may be limited to certain subgroup of patients. In addition, 5-10% of the asthmatics are not well-controlled by current drug treatment and they require oral steroids during exacerbation. Oral steroid usage is commonly associated with adverse effects.
Allergic asthma is a chronic airway disorder characterized by airway inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR) (1). Cumulative evidence revealed that these inflammatory responses are mediated by T-helper type 2 (Th2) cells together with mast cells, B cells and eosinophils, as well as a number of inflammatory cytokines and chemokines (1, 2). IL-4 is imperative for B cell isotype switching for the synthesis of immunoglobulin (Ig)E. Allergen-induced cross-linking of IgE-bound high affinity IgE receptors (FcεRI) on the surface of mast cells leads to degranulation and activation of mast cells, and the release of inflammatory mediators like histamine, leukotrienes and cytokines, and immediate bronchoconstriction (3, 4). IL-5 is vital for the growth, differentiation, recruitment, and survival of eosinophils which contribute to inflammation and even airway remodeling in asthma (5). IL-13 plays a pivotal role in the effector phase of Th2 responses such as eosinophilic inflammation, mucus hypersecretion, AHR and airway remodeling (6). In addition, chemokines such as RANTES (regulated on activation, normal T cells expressed and secreted) and eotaxin are crucial to the delivery of eosinophils to the airways (7). Airway eosinophilia, together with Th2 cytokines IL-4, IL-5 and IL-13, may ultimately contribute to AHR in asthma (8).
Chronic obstructive pulmonary disease (COPD) refers to chronic bronchitis and emphysema, two commonly co-existing diseases of the lungs in which the airways become narrowed (14). This leads to a limitation of the flow of air to and from the lungs causing shortness of breath. In contrast to asthma, the limitation of airflow is poorly reversible and usually gets progressively worse over time.
COPD is caused by noxious particles or gas, most commonly from tobacco smoking, which triggers an abnormal inflammatory response in the lung. The natural course of COPD is characterized by occasional sudden worsening of symptoms called acute exacerbations, most of which are caused by infections or air pollution. COPD is also known as chronic obstructive lung disease (COLD), chronic obstructive airway disease (COAD), chronic airflow limitation (CAL) and chronic obstructive respiratory disease (CORD).
There is currently no cure for COPD and the only measures that have been shown to reduce mortality are smoking cessation and supplemental oxygen (14). COPD can be managed with bronchodilators such as β2 agonists and/or anticholinergics. β2 agonist stimulate β2 receptors while anticholinergics block stimulation from cholinergic nerves both are medicines that relax smooth muscle around the airways, increasing air flow. There are several β2 agonists available, salbutamol or albuterol and terbutaline are widely used short acting β2 agonists and provide rapid relief of COPD symptoms. Long acting β2 agonists (LABAs) such as salmeterol and formoterol are used as maintenance therapy. Ipratropium is the most widely prescribed short acting anticholinergic drug. Anticholinergics appear to be superior to β2 agonists in COPD, however both β2 agonists and anticholinergics do not have anti-inflammatory actions and they do not halt progression of COPD.
PI3K is a family of lipid kinases comprising of 8 isoforms divided into 3 classes, of which class I enzymes are specific in phosphorylating phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), an ubiquitous second messenger that serves as a docking site for the activation of pleckstrin homology domain-containing kinases such as Akt. Class I PI3Ks are divided into class IA and class IB, and exist as heterodimers with catalytic subunits of class IA (p110α, p110β, and p110δ) and of class IB (p110γ) binding to regulatory subunits of class IA (p85α, p85β, p55γ, p55β or p50α) and of class IB (p101 or p84/p87), respectively (38). Of these, p110δ and p110γ PI3Ks are enriched in leukocytes and have been shown to play a critical role in the activation, proliferation, differentiation and migration of T and B lymphocytes, mast cells and eosinophils (18-20).
Artesunate is a semi-synthetic derivative of artemisinin, a sesquiterpene trioxane lactone isolated from the herb Artemisia annua. This medicinal plant has been used as a remedy for fevers and chills for centuries in China (9). Artemisinin derivatives including artesunate are anti-malarial drugs effective for both uncomplicated and severe malaria (9, 10). Besides this, Artemisinin derivatives have been shown to possess anti-cancer (11, 12), anti-viral (13), and anti-inflammatory (15 and 17) activities. Artesunate has been reported to block the production of IL-1β, IL-6 and IL-8 from TNF-α-stimulated human rheumatoid arthritis fibroblast-like synoviocytes (14). In addition, artesunate inhibits lipopolysaccharide-induced production of TNF-α, IL-6 and nitric oxide (NO), and expression of toll-like receptor 4 (TLR4) and TLR9 from macrophages (16, 18). The exact molecular mechanism that mediates these anti-inflammatory effects by artesunate has not been unequivocally determined. There are some evidence pointing to the inhibition of nuclear factor (NF)-κB transcriptional activity by artesunate and other artemisinin derivatives (15-17). More recently, artesunate has been found to possess strong inhibitory activity against the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway (12-14).
Artesunate is a derivative of artemisinin isolated from a Chinese herb Artemisia annua L. It is used clinically for the treatment of malaria. The structure of artesunate is depicted in FIG. 1. Artesunate is a well-tolerated drug approved for malaria therapy and, moreover, has an excellent safety profile demonstrated by extensive use as a malaria treatment.